Biological microscopy, explained

How can researchers get images and videos of activities in living cells? Kenneth Dunn, scientific director of the Indiana Center for Biological Microscopy, tells all. It’s impressive stuff, and it’s just cool to look at.

Straight Outta Helsinki: Eric Meslin and the bioethics of placebos

Fifty years ago the World Medical Association (WMA) adopted the Declaration of Helsinki, the world’s fundamental document laying out the ethical principles of medical research involving human subjects that physicians should follow. It has been widely adopted and serves as an important standard for many researchers around the world.

As you’d expect of a guideline that responds to changes in science and health, Helsinki has been modified since its creation in 1964. It has been amended seven times (with a further two “clarifying notes” added), most recently in 2013 for what has become the 50th anniversary edition. Some of the amendments have been pro forma, but others have addressed (and in turn raised) controversies in medical research. One of these stirred debate: the ethics of using placebos in research, especially in lower and middle income countries (LMIC).

“It’s been a tough debate,” says Eric Meslin, director of the IU Center for Bioethics.

The controversy was sparked in the late 1990s by complaints over a study, conducted by the AIDS Clinical Trials Group that was planned for sub-Saharan Africa and other locations, of a new drug regimen designed to prevent the transmission of HIV from infected mothers to their newborns. In the proposed trial, some mothers would receive the drug, while others would receive a placebo.

It is common to compare a new drug to a placebo, particularly when there is no other known treatment for the condition being studied. The trouble was in this case, another drug did exist – it had been tested in economically developed countries and had been shown to be very effective in reducing HIV transmission.  But it was prohibitively expensive. The hope was that a newer, less expensive drug could be found that still reduced HIV transmission.  The dilemma was whether to test the newer, less expensive drug against the proven expensive one (which was beyond the financial reach of patients in LMICs), or to test it against a placebo.  The argument for testing it against a placebo was that the mere existence of the more expensive drug was similar to there not being a drug at all. In these circumstances, the placebo was justified. But was it? When the alternative isn’t available due to cost, is the use of a placebo in a trial ethically acceptable?

When it updated the Declaration in 2000, the WMA said no. Debate and controversy ensued, and has not let up since even as several more revisions were made to Helsinki.

(Want some more background? Here’s a 2006 overview of the controversy from EMBO Reports, and some commentary from Meslin (PDF) in the October 2013 issue of the World Medical Journal (go to page 185).

So why is this a Vital Signs blog topic? Because during the Declaration of Helsinki revision process the association asked Meslin to comment on those thorny issues, during an August 2013 hearing in Washington, D.C. He spoke further about it at a meeting in Paris in February.

Bottom line, Meslin believes the 2013 Helsinki amendments are “perfectly fine,” but there were some missed opportunities. For one thing, he believes the Declaration needs to do a better job of anticipating changes in medical research that are likely to pose ethical quandaries in the future. For example, Meslin said, this version of the Declaration is the first to mention biobanking, though people at IU and elsewhere were planning and implementing biobanks a decade or more ago. The current version, meanwhile, says nothing about, say, nanotechnology.

And so, Meslin believes the process by which the Declaration is updated needs to change from its “ossified” state to one with more transparency — including the use of social media — and more frequency.

As for those placebo provisions, the wording has been tweaked, Meslin said, “but there’s still work to do.”

 

Translating science to scientists

So I headed out of my ink-stained office in the third floor of the ACME building over to Research 2 to meet Jie and Henrique — I’d heard they had new gigs with Science Translational Medicine. They were waiting for me. Unfortunately, they were waiting for me in Med Sci, a different building. After sorting things out (thanks, Cindy Booth!) we were able to meet up.

Jie Sun, assistant professor of pediatrics and of microbiology and immunology, and Henrique Serezani, assistant professor of microbiology and immunology, recently were selected to join a small group of associate scientific advisors for the translational medicine journal, a sister publication to the heavyweight journal Science.

Jie Sun and Henrique Serezani

Jie Sun and Henrique Serezani

Their job is to keep track of developments in their fields and once a month write a short summary of an interesting paper for the Journal’s Editor’s Choice section.

Sun’s research interests center on the regulation of immune response during acute respiratory virus infection. Serezani is interested in diabetes and sepsis — how sepsis, even after it’s been effectively treated, can leave patients susceptible to secondary infections.

Turns out, Sun’s first submission, reviewing a Nature paper on vaccine design, has already been published.

So what do they have in store for them? I tracked down Carmella Evans-Molina, assistant professor of medicine, who previously did a stint as an associate scientific advisor.

She enjoyed it, she said. It helped her keep up with the scientific literature. But the biggest benefit, she said, was to her writing. Each month she worked one-on-one with a journal editor who offered suggestions for her write-ups. “The articles needed to be written for non-experts, so overall, I think the clarity and quality of my writing improved significantly throughout the year.”

Fortunately for me, she decided to continue doing science, rather than switching to science writing. But back to Henrique and Jie.

I asked if they had collaborated on any research so far.

“No,” said Serezani. “But we’re working hard to find things to research in common. He’s becoming interested in diabetes. I’m also interested in diabetes. Not diabetes per se, but the morbidities associated with the disease.”

“Broadly, we’re both interested in acute infection in the context of chronic conditions,” said Sun.

“Yeah, yeah,” said Serezani. “That’s a good title for a grant, actually. Write that down and send it to me. Cool.”

“You think that may be too broad?” asked Sun.

“We’ll work it out.”

Maybe it’s like Rick at the end of Casablanca: “Louie, I think this is the beginning of a beautiful friendship.”Closing scene of Casablanca

Or at least, a grant application with a catchy title. Without Louie.

Wake up and get some sleep

It’s Friday and for a lot of folks, that means trying to use the upcoming weekend to catch up on sleep. It’s also near the end of National Sleep Awareness Week, which prompted the Indiana Psychological Association to offer some tips for better sleep, such as exercising regularly and avoiding near bedtime eating and alcohol consumption. Then maybe you won’t have to sleep in next Saturday.

Yelena Chernyak

Yelena Chernyak, IU School of Medicine

For more information, they suggest our own Yelena Chernyak, Ph.D., at the Behavioral Sleep Medicine Clinic in the Department of Psychiatry at IU School of Medicine at ycherna@iupui.edu.

While we’re at it, on the pediatric side IU School of Medicine faculty are there to help at the Riley Hospital for Children at IU Health Sleep Disorders Center.

And for more (and continuing) information about sleep check out the first in a series of articles on the importance of adequate sleep, and how to get it, available at our insideIU newsletter.

Unveiling the epigenetics of heart disease

Indianapolis can’t offer a nearby ocean, scenic bay or mountains, but new IU School of Medicine physician-scientist Ching-Pin Chang, M.D., Ph.D, says it’s offered something more important: the potential to expand his research horizons.

Ching-Pin Chang, M.D., Ph.D.

Ching-Pin Chang, M.D., Ph.D.

After 20 years at Stanford University, making important cardiovascular research discoveries and competing successfully for research grants, Dr. Chang joined the IU School of Medicine in the summer of 2013 as the new director of molecular and translational medicine at the Krannert Institute of Cardiology. Supported by resources from the Strategic Research Initiative and the Physician Scientist Initiative, he is applying his research discoveries in fetal heart development to adult heart disease and planning to move them into clinical trials.

Read the full story about Dr. Chang’s research here.

What’s a CIIS? Malaz Boustani explains

The new Center for Innovation and Implementation Science at Indiana University School of Medicine came online late in 2013, created to bring new health care solutions to the bedside faster and cheaper. Director Malaz Boustani explains how that’s supposed to work.

Update: They’ve changed the name. It’s now the Center for Health Innovation and Implementation Science. CHIIS.

 

 

Making a better mouse (model)

Mouse models of human disease are often key parts of biomedical research because they give scientists an opportunity to understand the origins and progression of a disease and begin testing potential therapies in ways that may not be possible with tests in cell cultures in the petri dish.

Wade Clapp (far right) and his colleagues

Wade Clapp (far right) and his colleagues

But often there is no appropriate mouse model — essentially a line of mice bred or manipulated to develop a human disease, or a close mouse counterpart. So researchers often will try to create the model they need.

That’s what Wade Clapp, M.D., and his IU School of Medicine colleagues did recently, getting some kudos from the Department of Defense in the process.

The disease is Neurofibromatosis type 2, which causes tumors — classified as low-grade, or slow-growing, malignancy — that primarily grow on the auditory nerve (but can appear on other nerves) resulting in hearing loss in teenagers or people in their 20s. The tumors can also cause balance problems, numbness and other problems depending on their location and size.

There had been mouse models of the disease but they didn’t develop the same sort of tumors as often seen in the human disease. So, with the assistance of a grant from the Department of Defense Neurofibromatosis Research Program, Dr. Clapp, who is chair of the IU Department of Pediatrics, and his colleagues have developed a mouse model that does develop the tumors and hearing loss that more closely resemble the human disease.

Dr. Clapp’s collaborators in the research were Su-Jung Park, Ph.D., assistant research professor of pediatrics, Charles Yates, M.D., assistant professor of clinical otolaryngology-head & neck surgery and M.D./Ph.D. student Jeff Gelhausen.

The mouse model should provide scientists with new tools to develop potential therapies for this rare but difficult disease that at the moment has no good treatment.

It will also add to the reputation of the Wells Center for Pediatric Research and IU Health Riley Hospital for Children as leaders in the research and treatment of neurofibromatosis, notably development of the first effective treatment for the tumors of neurofibromatosis type 1.

 

 

New technologies to study traumatic brain injury

Traumatic brain injuries frequently leave patients with problems both understanding others’ — and their own — emotions and controlling their emotional expressions. Now the newly opened IU InterFACE Center at Rehabilitation Hospital of Indiana combines advanced wireless technologies and innovative software with a living-room environment to help researchers and physicians get a better handle on what’s really going on when patients struggle with this issues. The center’s director, IU School of Medicine physician Dawn Neumann, and manager, Elena Gillespie, share some insights about the center in this video. As Elena says, think “Star Trek”:

 

 

Your face tells if you are sick

“A sick person has no poker face,” says IU School of Medicine emergency department physician Jeffrey Kline in a fascinating TEDxIndianapolis talk.

“By using our instincts, physicians can determine whether or not there’s a threat to life,” and a health care system focused on forms and expensive tests needs to accommodate that, he says.

 

From psoriasis to diabetes

Back in June we announced the first year results of a clinical trial in which alefacept, a drug originally sold to treat psoriasis, showed significant promise in blocking the  progression of type 1 diabetes among newly diagnosed patients.

Rigby_Mark_June2013

Mark Rigby, M.D., Ph.D.

Led by IUSM pediatrician Mark Rigby, the multi-center trial of 49 patients found that those receiving the drug were producing the same amount of insulin one year after diagnosis, while patients receiving a placebo injection were producing less, consistent with the deterioration that usually occurs after diagnosis with the disease.

The results were announced at the American Diabetes Association Scientific Sessions, and now have been published in The Lancet Diabetes & Endocrinology, accompanied by commentary by Kevan C Herold of Yale University who noted that “the evidence strongly supports clinical efficacy of this treatment strategy in the first year following diagnosis.” Unfortunately, as he also noted, the drug was withdrawn from the market by the manufacturer while the trial was under way. So its future as a potential clinical tool is unclear. See the BBC’s coverage here.